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1.
Tremika Le-Shan Wilson Namita Hattangady Antonio Marcondes Lerario Carmen Williams Erika Koeppe Shane Quinonez Jenae Osborne Kelly B. Cha Tobias Else 《Familial cancer》2017,16(4):561-566
Melanomas are associated with several hereditary conditions. We present a large family with several family members affected with primary melanomas and dysplastic nevi as well as thyroid cancer and other malignant tumors. Clinical work-up did not reveal a mutation in any of the genes usually considered with evaluation for predisposition to melanoma (BRCA1/2, CDKN2A, CDK4, PTEN, TP53). Whole exome sequencing of five affected family members showed a new variant in POT1. POT1 is associated with the telomere shelterin complex that regulates telomere protection and telomerase access. Germline mutations in POT1 were recently shown to be associated with hereditary predisposition to melanoma. Our findings support a role of POT1 germline mutations in cancer predisposition beyond melanoma development, suggesting a broader phenotype of the POT1-associated tumor predisposition syndrome that might also include thyroid cancer as well as possibly other malignant tumors. 相似文献
2.
Cecilie Heramb Teresia Wangensteen Eli Marie Grindedal Sarah Louise Ariansen Sheba Lothe Ketil Riddervold Heimdal Lovise Mæhle 《Hereditary cancer in clinical practice》2018,16(1):3
Background
Founder mutations in the two breast cancer genes, BRCA1 and BRCA2, have been described in many populations, among these are Ashkenazi-Jewish, Polish, Norwegian and Icelandic. Founder mutation testing in patients with relevant ancestry has been a cost-efficient approach in such populations. Four Norwegian BRCA1 founder mutations were defined by haplotyping in 2001, and accounted for 68% of BRCA1 mutation carriers at the time. After 15 more years of genetic testing, updated knowledge on the mutation spectrum of both BRCA1 and BRCA2 in Norway is needed. In this study, we aim at describing the mutation spectrum and frequencies in the BRCA1/2 carrier population of the largest clinic of hereditary cancer in Norway.Methods
A total of 2430 BRCA1 carriers from 669 different families, and 1092 BRCA2 carriers from 312 different families were included in a quality of care study. All variants were evaluated regarding pathogenicity following ACMG/ENIGMA criteria. The variants were assessed in AlaMut and supplementary databases to determine whether they were known to be founder mutations in other populations.Results
There were 120 different BRCA1 and 87 different BRCA2 variants among the mutation carriers. Forty-six per cent of the registered BRCA1/2 families (454/981) had a previously reported Norwegian founder mutation. The majority of BRCA1/2 mutations (71%) were rare, each found in only one or two families. Fifteen per cent of BRCA1 families and 25% of BRCA2 families had one of these rare variants. The four well-known Norwegian BRCA1 founder mutations previously confirmed through haplotyping were still the four most frequent mutations in BRCA1 carriers, but the proportion of BRCA1 mutation carriers accounted for by these mutations had fallen from 68 to 52%, and hence the founder effect was weaker than previously described.Conclusions
The spectrum of BRCA1 and BRCA2 mutations in the carrier population at Norway’s largest cancer genetics clinic is diverse, and with a weaker founder effect than previously described. As a consequence, retesting the families that previously have been tested with specific tests/founder mutation tests should be a prioritised strategy to find more mutation positive families and possibly prevent cancer in healthy relatives.3.
Background
Transforming growth factor β1 (TGFβ1) is a potent inhibitor of epithelial cell growth, thus playing an important role in tissue homeostasis. Most carcinoma cells exhibit a reduced sensitivity for TGFβ1 mediated growth inhibition, suggesting TGFβ1 participation in the development of these cancers. The tumor suppresor gene DPC4/SMAD4, which is frequently inactivated in carcinoma cells, has been described as a key player in TGFβ1 mediated growth inhibition. However, some carcinoma cells lacking functional SMAD4 are sensitive to TGFβ1 induced growth inhibition, thus requiring a SMAD4 independent TGFβ1 pathway.Results
Here we report that mature TGFβ1 is a ligand for the integrin αVβ6, independent of the common integrin binding sequence motif RGD. After TGFβ1 binds to αVβ6 integrin, different signaling proteins are activated in TGFβ1-sensitive carcinoma cells, but not in cells that are insensitive to TGFβ1. Among others, interaction of TGFβ1 with the αVβ6 integrin resulted in an upregulation of the cell cycle inhibitors p21/WAF1 and p27 leading to growth inhibition in SMAD4 deleted as well as in SMAD4 wildtype carcinoma cells.Conclusions
Our data provide support for the existence of an alternate TGFβ1 signaling pathway that is independent of the known SMAD pathway. This alternate pathway involves αVβ6 integrin and the Ras/MAP kinase pathway and does not employ an RGD motif in TGFβ1-sensitive tumor cells. The combined action of these two pathways seems to be necessary to elicit a complete TGFβ1 signal.4.
Bernholtz S Laitman Y Kaufman B Shimon-Paluch S Friedman E 《Breast cancer research and treatment》2012,132(2):669-673
BRCA1 and BRCA2 mutation carriers have an increased risk for developing breast (and ovarian) cancer. Non-carriers from within such families
(=true negatives) are counseled that their risk for developing breast cancer is similar to that of the average-risk population.
Breast cancer diagnosed in a non-carrier from a family with a known mutation is coined phenocopy. The rate of breast cancer
phenocopy and the risk for breast cancer in true negatives are unsettled. The rate of phenocopy breast cancer was assessed
in non-carriers from Jewish families with a BRCA1 or BRCA2 mutation, identified at the Sheba medical center. Analysis was performed by t test for comparison of mean age at counseling or breast cancer diagnosis, and by calculating a standardized incidence ratio
(SIR). Overall, 1318 females from 884 mutation carrying families (620 with BRCA1 264 with BRCA2 mutations) were genotyped, of whom 307 women from 245 families were assigned a true negative status (mean age at counseling
43.01 ± 13.03 years (range 19.7–92.8 years). Of these true negatives, 20 women (6.51–2.26% of families) developed breast cancer
at a mean age of 54.1 ± 12.9 years (range 48.1 –60.1 years). The SIR for breast cancer in true negatives was not significantly
different than the expected in the average-risk Israeli population [observed 20-expected 23.8 cases SIR = 0.84, 95% CI (0.51,
1.30)]. The rate of phenocopy breast cancer in non-carriers from Israeli BRCA1
BRCA2 mutation carrier families is 2.26% with no increased breast cancer risk over the average-risk population. 相似文献
5.
Transforming growth factor β (TGFβ) plays an important role in animal development and many cellular processes. A variety of cellular functions that are required for tumor metastasis are controlled by integrins, a family of cell adhesion receptors. Overexpression of αVβ6 integrin is associated with lymph node metastasis of gastric carcinomas. It has been demonstrated that a full TGFβ1 signal requires both αVβ6 integrin and SMAD pathway. TGFβ1 binds to αVβ6 via the DLXXL motif, a freely accessible amino acid sequence in the mature form of TGFβ1. Binding of mature TGFβ1 to αVβ6 leads to immobilization and tyrosine phosphorylation of proteins, which are associated with focal adhesions, a hallmark of integrin-mediated signal transduction. Here, we show that binding of mature TGFβ1 recruits the mitogen-activated protein kinase kinase kinase 1 (MEKK1), a mediator of c-Jun activation, and the extracellular signaling-regulated kinase-1 (Erk1) to focal adhesions. In addition, the p21-activated kinase 1 (PAK1) is associated with focal adhesions and differentially phosphorylated upon TGFβ1 stimulation. We conclude that TGFβ1 activates c-Jun via the MEKK1/p38 MAP kinase pathway and influences cytoskeletal organization. These finding may provide a link between TGFβ1 and the metastatic behavior of cancers. 相似文献
6.
Raissa Coelho Andrade Anna Claudia Evangelista dos Santos Joaquim Caetano de Aguirre Neto Julián Nevado Pablo Lapunzina Fernando Regla Vargas 《Familial cancer》2017,16(2):243-248
Li–Fraumeni and Li–Fraumeni like syndromes (LFS/LFL) represent rare cancer–prone conditions associated mostly with sarcomas, breast cancer, brain tumors, and adrenocortical carcinomas. TP53 germline mutations are present in up to 80 % of families with classic Li–Fraumeni syndrome, and in 20–60 % of families with Li–Fraumeni like phenotypes. The frequency of LFS/LFL families with no TP53 mutations detected suggests the involvement of other genes in the syndrome. In this study, we searched for mutations in TP53 in 39 probands from families with criteria for LFS/LFL. We also searched for mutations in the gene encoding the main mediator of p53 in cell cycle arrest, CDKN1A/p21, in all patients with no mutations in TP53. Eight probands carried germline disease-causing mutations in TP53: six missense mutations and two partial gene deletions. No mutations in CDKN1A coding region were detected. TP53 partial deletions in our cohort represented 25 % (2/8) of the mutations found, a much higher frequency than usually reported, emphasizing the need to search for TP53 rearrangements in patients with LFS/LFL phenotypes. Two benign tumors were detected in two TP53 mutation carriers: an adrenocortical adenoma and a neurofibroma, which raises a question about the possible implication of TP53 mutations on the development of such lesions. 相似文献
7.
8.
Objectives Regulatory T cells play an active role in the maintenance of the immune system’s tolerance of both foreign and self antigens.
Particularly, CD4
+ CD25
+ regulatory T cells participate in tumor immunity. The study provided further evidence on the involvement of CD4
+ CD25
+ regulatory T cells in immune system impairment in patients with gastrointestinal malignancies. Methods Using flow cytometry, CD4
+ CD25
+ regulatory T cells were analyzed in peripheral blood from 114 patients with gastrointestinal malignancies and 15 healthy
controls. Results The prevalence of the CD25
+ subset in CD4
+ T cells was increased in patients with colorectal carcinoma compared with healthy controls. The phenotic characteristics
of the CD4
+ CD25
+ T cells in patient with malignancies were low expression of CD45 RA and no expression of CD69. Our results indicated that when compared with healthy control, the proportions of CD4
+ CD25
+ T cells in the peripheral blood of patients with colorectal, gastric, and esophageal carcinoma were significantly higher
(P < 0.05) in colorectal carcinoma (22.11 ± 9.65%), gastric carcinoma (17.74 ± 4.24%), and esophageal carcinoma (24.37 ± 4.82)%,
respectively. Further analysis on the proportion of CD4
+ CD25
+ T cells revealed that those patients with gastrointestinal malignancies in stages IV were higher than those of in stage I–III,
though no significant difference was observed (P > 0.05). However, the proportion of CD4
+ CD25
+ T cells in the patients with relapse gastric carcinoma (23.32 ± 4.98%) was significantly higher than that of patients with
primary gastric carcinoma (P < 0.01). Conclusions The increased CD4
+ CD25
+ T cells in patients with gastrointestinal malignancies may be related to immunosuppression and tumor progression. This suggests
that elimination or reduction of CD4
+ CD25
+ regulatory T cells can improve effective tumor immunity for immunotherapy. 相似文献
9.
Gutiérrez-Enríquez S Balmaña J Baiget M Díez O 《Breast cancer research and treatment》2008,107(3):455-457
10.
Eli Marie Grindedal Harald Aarset Inga Bj?rnevoll Elin R?yset Lovise M?hle Astrid Stormorken Cecilie Heramb Heidi Medvik P?l M?ller Wenche Sjursen 《Hereditary cancer in clinical practice》2014,12(1):12
Background
Using immunohistochemistry (IHC) to select cases for mismatch repair (MMR) genetic testing, we failed to identify a large kindred with the deleterious PMS2 mutation c.989-1G > T. The purpose of the study was to examine the sensitivity of IHC and microsatellite instability-analysis (MSI) to identify carriers of the mutation, and to estimate its penetrance and expressions.Methods
All carriers and obligate carriers of the mutation were identified. All cancer diagnoses were confirmed. IHC and MSI-analysis were performed on available tumours. Penetrances of cancers included in the Amsterdam and the Bethesda Criteria, for MSI-high tumours and MSI-high and low tumours were calculated by the Kaplan-Meier algorithm.Results
Probability for co-segregation of the mutation and cancers by chance was 0.000004. Fifty-six carriers or obligate carriers were identified. There was normal staining for PMS2 in 15/18 (83.3%) of tumours included in the AMS1/AMS2/Bethesda criteria. MSI-analysis showed that 15/21 (71.4%) of tumours were MSI-high and 4/21 (19.0%) were MSI-low. Penetrance at 70 years was 30.6% for AMS1 cancers (colorectal cancers), 42.8% for AMS2 cancers, 47.2% for Bethesda cancers, 55.6% for MSI-high and MSI-low cancers and 52.2% for MSI-high cancers.Conclusions
The mutation met class 5 criteria for pathogenicity. IHC was insensitive in detecting tumours caused by the mutation. Penetrance of cancers that displayed MSI was 56% at 70 years. Besides colorectal cancers, the most frequent expressions were carcinoma of the endometrium and breast in females and stomach and prostate in males. 相似文献11.
Youlia M. Kirova Alexia Savignoni Brigitte Sigal-Zafrani Anne de La Rochefordiere Rémy J. Salmon Pascale This Bernard Asselain Dominique Stoppa-Lyonnet Alain Fourquet 《Breast cancer research and treatment》2010,119(1):119-126
As tumours in BRCA1/2 mutation carriers might be more sensitive to radiation, we investigated after long-term follow-up whether mutation status
influenced the rate of ipsilateral and contralateral breast cancers after breast-conserving treatment (BCT). BRCA1 and BRCA2 genes were screened for germline mutations in 131 patients with a family history of breast and/or ovarian cancer who had
undergone BCT and radiotherapy. Patients were matched to 261 controls with sporadic breast cancer according to age at diagnosis
and year of treatment. Controls were followed up for at least as long as the interval between diagnosis and genetic screening
in familial cases. Rates of ipsilateral and contralateral cancer between groups were compared by the log-rank test. The BRCA1/2 mutations occurred in 20.6% of tested patients. Tumours in mutation carriers were more likely to be grade III (P < 10−4) and oestrogen receptor negative (P = 0.005) than in non-carriers and controls. Overall median follow-up was 161 months. There was no significant difference
in ipsilateral tumours between mutation carriers, non-carriers and controls (P = 0.13). On multivariate analysis, age was the most significant predictor for ipsilateral recurrence (P < 10−3). The rate of contralateral cancer was significantly higher in familial cases: 40.7% (mutation carriers), 20% (non-carriers),
and 11% (controls) (P < 10−4). After 13.4 years of follow-up, the rate of ipsilateral tumours was no higher in mutation carriers than in non-carriers
or controls. As tumours in BRCA1/2 mutation carriers might be more sensitive to radiation, BCT is a possible treatment option. 相似文献
12.
Lee KM Park SK Hamajima N Tajima K Yoo KY Shin A Noh DY Ahn SH Hirvonen A Kang D 《Breast cancer research and treatment》2005,90(2):149-155
Objective. The proliferation of malignant breast epithelial cells is regulated by various stimuli including cytokines and growth factors, thus the variants of those genes may modify the breast cancer risk. To evaluate the potential influences of TGF-1 T29C and TNF- A252G gene polymorphisms on breast cancer risk, a case–control study was conducted in Korea.Methods. Histologically confirmed breast cancer cases (n = 560) and controls (n=509) with no previous history of cancer were recruited from three teaching hospitals in Seoul, Korea. Genotypes were determined by PCR-CTPP (polymerase chain reaction with confronting two-pair primers) method. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression model adjusting for age, body mass index, education, parity, age at first full-term pregnancy, and family history of breast cancer. Results. The TGF-1 29C-allele containing genotypes posed an increased risk of breast cancer (OR=1.3, 95% CI=1.02–1.79), especially in postmenopausal women (OR=1.6, 95% CI=1.01–2.44). Similarly, the TNF- 252G-allele containing genotypes posed an increased risk of postmenopausal breast cancer (OR=1.7, 95% CI=1.09–2.55). The risk of postmenopausal breast cancer increased in parallel with the number of the risk genotypes (p for trend <0.01). When data were stratified by the presumed non-genetic risk factors, TGF-1 C-allele containing genotypes were found to increase breast cancer risk almost two-fold in postmenopausal women with greater than median body mass index (>22.8 kg/m2) (OR=1.9, 95% CI=1.04–3.37).Conclusion. The results of this study therefore suggest that polymorphisms of TGF-1 and TNF- genes may modify individual susceptibility to breast cancer in Korean women. 相似文献
13.
Thomas V. O. Hansen Ane Y. Steffensen Lars Jønson Mette K. Andersen Bent Ejlertsen Finn C. Nielsen 《Breast cancer research and treatment》2010,119(3):547-550
Germ-line mutations in BRCA2 predispose to breast and ovarian cancer. Mutations are widespread throughout the gene and include disease-causing mutations
as frameshift, nonsense, splicing mutations and large genomic rearrangements. However a large number of mutations, including
missense, silent and intron variants are of unknown significance. Here, we describe the functional characterization of a silent
mutation (nucleotide 744 G → A/c.516 G → A, Lys172Lys) in exon 6 of BRCA2 in a Danish family with breast and ovarian cancer. Exon trapping analysis showed that the mutation results in skipping of
exon 6 and/or both exon 5 and 6, which was verified by RT-PCR analysis on RNA isolated from whole blood of the affected patient.
We therefore conclude that the BRCA2 silent mutation Lys172Lys is a disease-causing mutation. 相似文献
14.
Zhang L Gu L Qian B Hao X Zhang W Wei Q Chen K 《Breast cancer research and treatment》2009,114(2):327-338
Estrogen plays a role in breast cancer development, and genetic polymorphisms in estrogen receptor gene ER-α and genes regulating estrogen biosynthesis and metabolisms are associated with the risk of breast cancer in women in western
countries. Therefore, we hypothesized that SNPs in ER-α and other estrogen-metabolizing genes contribute to breast cancer risk in Chinese women. In this study, we genotyped polymorphisms
in the regulatory regions of ER-α (rs3798577) and other two estrogen-metabolizing enzyme genes CYP17 (rs743572) and CYP19 (rs10046) among 300 breast cancer cases and 390 controls in a Chinese population. Crude and adjusted odds ratios (aORs) and
95% confidence intervals (CIs) were calculated by unconditional logistic regression analyses to estimate breast cancer risk
associated with these polymorphisms. We found that the T allele frequency of ER-α was significantly higher in cases (59.8%) than controls (54.5%) (P = 0.047), but no significant difference was found in the genotype distribution. However, postmenopausal breast cancer risk
was associated with the CYP17 TC genotype (aOR = 1.77, 95% CI = 1.11–2.83) compared with the TT genotype. The CYP19 variant TC + TT genotypes were associated with both overall cancer risk (TT + TC vs. TT aOR = 1.73, 95% CI = 1.13–2.65) and
premenopausal cancer risk (TT + TC vs. TT aOR = 1.78, 95% CI = 1.03–3.09), particularly for ER +/PR + tumors. Furthermore,
there were joint effects between CYP19 T and ER-α T varint genotypes (aOR = 1.67, 95% CI = 1.03–2.69 for CYP19 TC + TT vs. CC among ER-α T variant carriers) and between CYP19 T and CYP17 C variant genotypes (aOR = 1.77, 95% CI = 1.11–2.83 for CYP19 TC + TT vs. CC among CYP17 variant C carriers). This study provides evidence that polymorphisms CYP17 rs743572, CYP19 rs10046 and ER-α rs3798577 are associated with breast cancer risk among Chinese women. 相似文献
15.
16.
17.
Are <Emphasis Type="Italic">BRCA1</Emphasis>- and <Emphasis Type="Italic">BRCA2</Emphasis>-related breast cancers associated with increased mortality?
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There has been contradictory evidence as to whether BRCA1 associated breast cancers have a poorer prognosis than non-BRCA1 cancers. In this issue of Breast Cancer Research Robson and colleagues provide further evidence for poorer survival in BRCA1 carriers and show that it could be attributed to failure to treat small node-negative grade 3 breast cancers with chemotherapy. There still remains little evidence for a survival difference for BRCA2 related breast cancers. Although the high contralateral breast cancer risk is confirmed by this study there is no real evidence for an increase in ipsilateral recurrence or new primary breast cancers in mutation carriers up to the 10-year point. 相似文献
18.
Kamagata C Tsuji N Moriai M Kobayashi D Watanabe N 《Breast cancer research and treatment》2007,102(3):263-273
The cyclopentenone prostaglandin 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) exerts a growth inhibitory effect on cancer cells, and this effect is linked to the induction of apoptosis or cell cycle
arrest. Induction of apoptosis by 15d-PGJ2 is associated with the down-regulation of anti-apoptotic proteins. G0-G1→S phase progression is inhibited by 15d-PGJ2 via the degradation of cyclin D1. In this study, we further investigated the mechanism by which 15d-PGJ2 inhibits cancer cell growth by using the breast cancer cell lines MCF-7 and T-47D. Treatment with 20 μM 15d-PGJ2 for 72 h completely blocked the growth in both cell lines. However, the proportions of apoptotic MCF-7 and T-47D cells were
21.1% and 40.9%, respectively, indicating that the induction of apoptosis did not appear to fully account for growth inhibition
by 15d-PGJ2. Cell cycle analysis using cells synchronized at the G0-G1 or S phase revealed that 15d-PGJ2 blocked not only G0-G1→S phase progression but also G2-M phase progression. The expression of both cyclins D1 and B1 was decreased by 15d-PGJ2. Furthermore, 15d-PGJ2 inhibited aurora-B kinase activity, which coincided with the down-regulation of survivin. Thus, 15d-PGJ2 induced cell cycle arrest at the G2-M phase via inhibition of cyclin B1 expression and aurora-B kinase activity. We conclude that survivin may be an important
target for 15d-PGJ2, and its down-regulation may lead to a decrease in aurora-B kinase activity.
Naoki Tsuji substantially contributed to this work and should also be considered a first author. 相似文献
19.
Paul C. Johannesma Arjan C. Houweling Fred H. Menko I. van de Beek Rinze Reinhard Johan J. P. Gille JanHein T. M. van Waesberghe Erik Thunnissen Theo M. Starink Pieter E. Postmus R. Jeroen A. van Moorselaar 《Familial cancer》2016,15(2):297-300
Renal cell cancer (RCC) represents 2–3 % of all cancers and is the most lethal of the urologic malignancies, in a minority of cases caused by a genetic predisposition. Birt–Hogg–Dubé syndrome (BHD) is one of the hereditary renal cancer syndromes. As the histological subtype and clinical presentation in BHD are highly variable, this syndrome is easily missed. Lung cysts—mainly under the main carina—are reported to be present in over 90 % of all BHD patients and might be an important clue in differentiating between sporadic RCC and BHD associated RCC. We conducted a retrospective study among patients diagnosed with sporadic RCC, wherein we retrospectively scored for the presence of lung cysts on thoracic CT. We performed FLCN mutation analysis in 8 RCC patients with at least one lung cysts under the carina. No mutations were identified. We compared the radiological findings in the FLCN negative patients to those in 4 known BHD patients and found multiple basal lung cysts were present significantly more frequent in FLCN mutation carriers and may be an indication for BHD syndrome in apparent sporadic RCC patients. 相似文献
20.
Julián Esteban Londo?o Hernández Marcia Llacuachaqui Gonzalo Vásquez Palacio Juan David Figueroa Jorge Madrid Mauricio Lema Robert Royer Song Li Garrett Larson Jeffrey N Weitzel Steven A Narod 《Hereditary cancer in clinical practice》2014,12(1):11